Abstract
The fusion kinases of ROS1 and ALK have been identified as oncogene drivers in small portions of many malignancies, especially in non-small cell lung cancer (NSCLC). ALK/ROS1/MET inhibitor crizotinib has been approved by the US Food and Drug Administration for the treatment of ALK or ROS1-positive non-small cell lung cancer in 2011 and 2016, respectively. The emergence of drug resistance presents a major issue for targeted therapy. Although ceritinib, alectinib, and brigatinib have been approved for crizotinib-refractory ALK+ patients with NSCLC, treatment options for patients with ROS1+ NSCLC are limited, especially for crizotinib-refractory patients. Ceritinib and entectinib demonstrated clinical efficacy only in crizotinib-naïve ROS1+ patients. The most common resistance mechanisms to crizotinib treatment in ROS1+ NSCLC is the solvent front mutation ROS1 G2032R and gatekeeper mutation ROS1 L2026M. TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ROS1 inhibitors in the clinic, was designed to overcome clinical resistance mutations systematically. TPX-0005 potently inhibited both wild type and mutant ROS1s including solvent front mutations and gatekeeper mutations. TPX-0005 showed pico-molar activity against ROS1 kinase (IC50 0.076 nM) in Reaction Biology kinase assay. The comparison of TPX-0005 with other ROS1 inhibitors in Ba/F3 cell proliferation assays is presented in the table. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor regression in the tumors carrying WT or solvent-front mutated ROS1 fusion gene. Overall, TPX-0005 demonstrated desired drug-like properties, good safety profile, and is a supreme ROS1 inhibitor against WT and various mutated ROS1s. A phase 1/2 clinical trial of TPX-0005 is actively being pursued (NCT03093116).
CD74-ROS1 Ba/F3 Cell Proliferation Assay IC50 (nM) | ||||||
Inhibitor | WT | G2032R | D2033N | L2026M | S1986F | S1986Y |
TPX-0005 | <0.2 | 8.4 | 0.2 | 10 | <0.2 | <0.2 |
Crizotinib | 9.7 | 1402 | 139 | 606.4 | 20.9 | 19 |
Lorlatinib | 0.5 | 262.4 | 2.4 | ND | 0.3 | 0.3 |
Entrectinib | 25.4 | 2404 | ND | 2026 | ND | ND |
Ceritinib | 131.9 | 2000 | ND | ND | 14.2 | 26.9 |
Brigatinib | 28.6 | 1385 | 167.1 | 2115 | 27.7 | 24.6 |
Cabozantinib | 1.0 | 60.7 | 0.1 | 29.1 | ND | ND |
CD74-ROS1 Ba/F3 Cell Proliferation Assay IC50 (nM) | ||||||
Inhibitor | WT | G2032R | D2033N | L2026M | S1986F | S1986Y |
TPX-0005 | <0.2 | 8.4 | 0.2 | 10 | <0.2 | <0.2 |
Crizotinib | 9.7 | 1402 | 139 | 606.4 | 20.9 | 19 |
Lorlatinib | 0.5 | 262.4 | 2.4 | ND | 0.3 | 0.3 |
Entrectinib | 25.4 | 2404 | ND | 2026 | ND | ND |
Ceritinib | 131.9 | 2000 | ND | ND | 14.2 | 26.9 |
Brigatinib | 28.6 | 1385 | 167.1 | 2115 | 27.7 | 24.6 |
Cabozantinib | 1.0 | 60.7 | 0.1 | 29.1 | ND | ND |
ND: not determined.
Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John Lim, Yishan Li. TPX-0005, a supreme ROS1 inhibitor, overcomes crizotinib-resistant ROS1 mutations including solvent front mutation G2032R and gatekeeper mutation L2026M [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B185.